Note: Descriptions are shown in the official language in which they were submitted.
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PETROLATUM-BASED COMPOSITIONS AND METHODS OF TREATMENT FOR
ONYCHOMYCOSIS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application
Serial
Number 62/793,317, entitled "Petrolatum-Based Compositions and Methods of
Treatment for
Onychomycosis," filed January 16, 2019, the contents of which are incorporated
by reference
herein, for all purposes, in its entirety.
FIELD
[0002] The present disclosure is broadly concerned with petrolatum-based
compositions for the treatment and prevention of onychomycosis. The disclosure
is also
concerned with methods for the treatment of onychomycosis using petrolatum-
based
compositions.
BACKGROUND
[0003] Onychomycosis, also known as tinea unguium, is a highly prevalent
fungal
infection of the nail affecting 35 million people in the United States.
Without treatment,
onychomycosis may damage the nail unit and spread to other fingers or toes and
skin.
Onychomycosis affects 1 in 3 diabetics and increases the risk of secondary
infections which may
lead to foot disorders and limb amputations. Since, onychomycosis is generally
a non-life
threatening infection, it should ideally be treated topically. However,
current topical treatments
do not penetrate the nail plate rendering them ineffective due to an inability
to reach microbes
below the nail plate. The use of oral medications for onychomycosis are
limited by safety
concerns including liver toxicity, drug-drug interactions, loss of taste, and
migraine headaches.
As a result, 85% of the 1 in 10 Americans affected by onychomycosis fail to
seek treatment due
to limited safe and effective treatment options. Accordingly, additional
compositions and
methods for the treatment of onychomycosis are desirable.
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BRIEF DESCRIPTION OF THE FIGURES
[0004] The application file contains at least one photograph executed in
color. Copies
of this patent application publication with color photographs will be provided
by the Office upon
request and payment of the necessary fee.
[0005] FIG. 1 depicts an electron microscope micrograph showing the structure
of
typical nails, according to an exemplary embodiment of the present disclosure.
[0006] FIG. 2 is a diagrammatic view depicting penetration of the presently
disclosed
topical compositions through the nail to deliver one or more anti-fungal
agents to the site of
infection below the nail, according to an exemplary embodiment of the present
disclosure.
DETAILED DESCRIPTION
[0007] The present disclosure provides compositions and methods for the
treatment of
onychomycosis. It has been unexpectedly discovered that the presently
disclosed compositions
comprising one or more anti-fungal agents dispersed as nanodroplets in a
petrolatum carrier are
effective in the treatment of onychomycosis. In particular, it has been
unexpectedly discovered
that the presently disclosed compositions are capable of penetrating the
keratin surface and nail
plate to deliver a pharmaceutically effective amount of anti-fungal agent
directly to the site of
infection. In particular, as depicted in FIG. 1, the presently disclosed
compositions are capable
of penetrating the keratin surface of the nail to carry active ingredients,
such as anti-fungal
agents, through the channels of the lipid bilayers and deliver the active
ingredients to the nail bed
and throughout the nail itself. FIG. 1 depicts an electron micrograph of skin
or nail comprising
corneocytes interspaced by intercellular lipid bilayers. As shown in FIG. 2,
water-based topical
formulations cannot penetrate the corneocytes nor pass through the
intercellular lipids
interspersed between the corneocytes. However, the presently disclosed
petrolatum-based
compositions are capable of passing through the intercellular lipid channels
to penetrate the
epidermal layer and enable deep delivery of antifungal ingredients, such as
one or more anti-
fungal agents, to the site of the infection below the nail.
[0008] According to at least one aspect of the present disclosure, a method of
treating
onychomycosis in a subject is provided. The method may include applying a
petrolatum-based
composition to the nail of a subject in need of treatment. The petrolatum-
based composition may
include a pharmaceutically effective amount of one or more anti-fungal agents
in a petrolatum
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carrier. In at least some instances, the one or more anti-fungal agents is
dispersed in the
petrolatum carrier to form a stable petrolatum-based suspension. In some
cases, the one or more
anti-fungal agents is dispersed in the petrolatum carrier in the form of
nanodroplets. The
nanodroplets may comprise, for example, one or more fungal agents and a polar
solvent. For
instance, the one or more anti-fungal agents may be dissolved in a polar
solvent to form an anti-
fungal agent solution and the anti-fungal agent solution dispersed in the
petrolatum to form a
stable suspension. The one or more anti-fungal agents may include, for
example, terbinafine
HC1, ciclopirox, ciclopirox olamine, fluconazole, itraconazole, ketoconazole,
amorolfine,
efinaconazole, clotrimazole, miconazole (miconazole nitrate), and any
combination thereof.
[0009] In at least some instances, the onychomycosis may be distal subungual
onychomycosis, or white superficial onychomycosis (WSO), or proximal subungual
onychomycosis, or Candidal onychomycosis. In some cases, the onychomycosis may
be caused
by Trichophyton rubrum (T. rubrum), or caused by Candida, or caused by Candida
auris (C.
auris). In at least some instances, the onychomycosis may be caused by multi-
drug resistant C.
auris.
[0010] The presently disclosed petrolatum-based composition may include, for
example, greater than about 80% by weight petrolatum, or greater than about
90% by weight
petrolatum, or greater than about 95% by weight petrolatum. The petrolatum-
based composition
may include from about 0.05% to about 5% by weight of the one or more anti-
fungal agents, or
from about 0.05% to about 3% by weight of the one or more anti-fungal agents,
or from about
0.1% to about 1% by weight of the one or more anti-fungal agents, or from
about 0.2% to about
0.6% by weight of the one or more anti-fungal agents, or from about 0.3% to
about 0.5% by
weight of the one or more anti-fungal agents, or from about 0.1% to about 3.5%
by weight of the
one or more anti-fungal agents, or from about 0.05% to about 2.5% by weight of
the one or more
anti-fungal agents, or from about 0.5% to about 3% by weight of the one or
more anti-fungal
agents, or from about 0.5% to about 2.5% by weight of the one or more anti-
fungal agents, or
from about 1.5% to about 2.5% by weight of the one or more anti-fungal agents.
In at least some
instances, the petrolatum-based composition contains no emulsifier. In other
instances, the
petrolatum-based composition excludes an added emulsifier. As used herein, the
term "added
emulsifier" refers to an emulsifier in addition to the presently claimed
components of the
petrolatum-based composition.
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[0011] In at least some instances, the petrolatum-based composition may
further
include a cationic biocide selected from the group consisting of benzalkonium
chloride,
cetrimide, chlorhexidine, and any combination thereof. In some instances, the
petrolatum-based
composition may include from about 0.001% to about 0.15% by weight
benzalkonium chloride
(BZK), or from about 0.001% to about 0.01% by weight BZK, or from about 0.005%
to about
0.007% by weight BZK. In at least some instances, the presently disclosed
petrolatum-based
compositions may be prepared by a process that includes: (a) dissolving the
one or more anti-
fungal agents in a polar solvent to give a anti-fungal agent solution; (b)
heating the petrolatum to
a temperature sufficient to cause the petrolatum to melt to give a melted
petrolatum and heating
the anti-fungal agent solution to a temperature higher than the temperature of
the melted
petrolatum to give a heated anti-fungal agent solution; (c) mixing the melted
petrolatum and the
heated anti-fungal agent solution to give a melted mixture; and (d) cooling
the melted mixture to
give the petrolatum-based composition. In some instances, the heated anti-
fungal agent solution
may have a temperature that is about 1 C to about 5 C higher than the
temperature of the melted
petrolatum. In some instances, the one or more anti-fungal agents are
dissolved in a polar
solvent to form an anti-fungal agent solution and the anti-fungal agent
solution is dispersed in the
petrolatum to form a stable suspension.
[0012] In at least some instances, the petrolatum-based compositions may
include from
about 0.01% to about 5% by weight terbinafine HC1, or from about 0.01% to
about 5% by weight
ciclopirox, or from about 0.01% to about 5% by weight ciclopirox olamine, or
from about 0.01%
to about 5% by weight fluconazole, or from about 0.01% to about 5% by weight
itraconazole, or
from about 0.01% to about 5% by weight ketoconazole, or from about 0.01% to
about 5% by
weight amorolfine, or from about 0.01% to about 5% by weight efinaconazole, or
from about
0.01% to about 5% by weight clotrimazole, or from about 0.01% to about 5% by
weight
miconazole (miconazole nitrate), or any combination thereof.
[0013] According to at least one aspect of the present disclosure, the
petrolatum-based
composition may be a petrolatum-based composition that includes petrolatum and
a
pharmaceutically effective amount of one or more anti-fungal agents. In such
cases, the
compositions may include, for example, greater than about 80% by weight
petrolatum. The
compositions may also include a polar solvent. In some instances, the polar
solvent may be
water. In certain cases, the one or more anti-fungal agents and the polar
solvent may be
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dispersed in the petrolatum in the form of nanodroplets. According to at least
one aspect, the
petrolatum-based compositions contain no emulsifier. In some instances, the
one or more anti-
fungal agents may be dissolved in a polar solvent to form an anti-fungal agent
solution and the
anti-fungal agent solution dispersed in the petrolatum. In such cases, the
anti-fungal agent
solution may be dispersed in the petrolatum to form a stable suspension such
that the anti-fungal
agent solution does not separate from the petrolatum for at least six months.
According to at
least one aspect of the present disclosure, the resultant petrolatum-based
compositions do not
require an emulsifier to form a stable suspension of one or more anti-fungal
agents dispersed in
the petrolatum. Further, the petrolatum-based compositions prepared according
to this process
does not require high shear mixing to form a stable suspension of one or more
anti-fungal agents
in petrolatum in the absence of an added emulsifier.
I. COMPOSITIONS
[0014] According to one aspect, the present disclosure provides for
compositions that
are petrolatum-based. A petrolatum-based composition is made up primarily of
petrolatum. The
characteristics of a petrolatum-based composition differ from a composition
containing only a
small amount of petrolatum. In some embodiments, the petrolatum-based
composition is greater
than about 80% petrolatum. In other embodiments, the petrolatum-based
composition is greater
than about 81% petrolatum, greater than about 82% petrolatum, greater than
about 83%
petrolatum, greater than about 84% petrolatum, greater than about 85%
petrolatum, greater than
about 86% petrolatum, greater than about 87% petrolatum, greater than about
88% petrolatum,
greater than about 89% petrolatum, greater than about 90% petrolatum, greater
than about 91%
petrolatum, greater than about 92% petrolatum, greater than about 93%
petrolatum, greater than
about 94% petrolatum, greater than about 95% petrolatum, greater than about
96% petrolatum,
greater than about 97% petrolatum, greater than about 98% petrolatum, or
greater than about
99% petrolatum. The petrolatum is preferably medical grade petrolatum.
[0015] The composition also contains one or more anti-fungal agents dispersed
throughout the petrolatum. The one or more anti-fungal agents are the
composition ingredient
active in treating onychomycosis. In addition to the one or more anti-fungal
agents, the presently
disclosed compositions may also include cationic biocides, such as quaternary
ammonium
compounds, bisbiguanides, and polymeric biguanides. In particular, other
cationic biocides that
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may be included in the compositions may include, but are not limited to,
benzalkonium chloride,
cetrimide, chlorhexidine, polihexanide biguanide (polihexanide,
polyhexamethylene guanide,
poly(iminoimidocarbonyl-iminoimidocarbonyl-iminohexamethylene),
poly(hexamethylenebiguanide), polyaminopropyl biguanide) and salts or
combinations thereof.
In some instances, the presently disclosed compositions contain benzalkonium
chloride (BZK) as
a preservative. The total amount of cationic biocide in the composition
generally constitutes less
than about 1% by weight of the total composition. In preferred embodiments,
the cationic biocide
constitutes from about 0.1% to about 0.5% by weight, or more preferably, from
about 0.1% to
about 0.3% by weight to the total composition.
[0016] The remaining weight of the composition, typically from about 0.1% to
about
6% by weight of the petrolatum-based composition, is liquid. In some
instsances, the
composition contains about 5% water.
[0017] The one or more anti-fungal agents and cationic biocides that may be
used in
the presently disclosed compositions do not react with the petrolatum.
Instead, the one or more
anti-fungal agents and optional cationic biocides that may be included in the
compositions are
dispersed in the petrolatum as nanodroplets, and the petrolatum serves as a
suspension matrix for
the one or more anti-fungal agents and cationic biocides. "Nanodroplet," as
used herein, is an
aggregation of one or more anti-fungal agents and optionally any cationic
biocide molecules in
the petrolatum base. The nanodroplets typically contain a small amount of
water or other polar
solvent in addition to the one or more anti-fungal agents and optional
cationic biocides.
Nanodroplets in accordance with the present disclosure may vary in size but
generally the
longest dimension of the nanodroplets measures from about 10 nm to about
10,000 nm. In
various embodiments, the nanodroplets range from about 10 nm to about 100 nm,
from about
100 nm to about 1000 nm, from about 1000 nm to about 2000 nm, from about 2000
nm to about
3000 nm, from about 3000 nm to about 4000 nm, from about 4000 nm to about 5000
nm, from
about 5000 nm to about 6000 nm, from about 6000 nm to about 7000 nm, from
about 7000 nm to
about 8000 nm, from about 8000 nm to about 9000 nm, from about 9000 nm to
about 10,000 nm.
The nanodroplets are dispersed through the petrolatum homogeneously.
[0018] Surprisingly, embodiments of the present invention do not require an
emulsifier.
An emulsifier, as used herein, is an added formulation ingredient used to
reduce the tension
between hydrophilic and hydrophobic surface ingredients, thereby facilitating
the mixture
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hydrophilic and hydrophobic ingredients. Prior to the present invention, those
skilled in the art
expected that an emulsifier would be needed to disperse polar ingredients,
such as a polar
solvent, one or more anti-fungal agents, and cationic biocides, in a non-polar
petrolatum
suspension matrix. Where an emulsifier is used, the emulsifier may have a
hydrophilic-
lipophilic balance (HLB) of less than 10.
[0019] The compositions described herein are stable. In one aspect, stability
refers to
the integrity of the composition as a whole, and in particular, the stability
of the nanodroplets in
the petrolatum. Under ambient conditions, the petrolatum and the one or more
anti-fungal agents
and optional cationic biocides will not separate for greater than two years,
meaning that the
composition is shelf stable for at least two years. Even under accelerated
conditions, such as
reduced pressure, the petrolatum and the one or more anti-fungal agents and
optional cationic
biocides do not separate, but rather the one or more anti-fungal agents and
optional cationic
biocides remain suspended as nanodroplets in the petrolatum. In addition to
the stability of the
nanodroplets within the composition, the compositions described herein also
show exceptional
chemical stability for the one or more anti-fungal agents and optional
cationic biocides. The
chemical stability stems primarily from the low-temperature manufacturing
process described
below. The absence of excessive heat conditions in the manufacturing of the
compositions
improves the chemical stability (resistance to degradation) for the one or
more anti-fungal agents
and optional cationic biocides.
[0020] According to at least one aspect of the present disclosure, the
petrolatum-based
compositions described herein consist essentially of petrolatum, one or more
anti-fungal agents,
and water. In at least one embodiment, the petrolatum-based compositions
consist essentially of
petrolatum, one or more anti-fungal agents, benzalkonium chloride, and water.
In alternative
embodiments, the petrolatum-based compositions described herein consist of
petrolatum, a
cationic biocide, and one or more anti-fungal agents.
[0021] In other embodiments, the petrolatum-based compositions described
herein may
further comprise a compound that stimulates healing. More specifically, the
petrolatum-based
compositions described herein may further comprise a compound that stimulates
healing for use
in intraoperative applications and chronic wound care applications. Non-
limiting examples of
compounds that stimulate healing include polycaprolactone-tricalcium phosphate
(PCL-TCP),
collagen, chitosan, cellulose, thrombin, chondroitin sulfate (CS), chondroitin
sulfate
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succinimidyl succinate (CS-NHS), and growth factors such as TGF-alpha, TGF-
beta (TGF(31,
TGF(32, TGF(33), platelet-derived growth factor (PDGF), epidermal growth
factor (EGF),
fibroblast growth factor also referred to as keratinocyte growth factor (FGF1,
FGF2, FGF4,
FGF7), vascular endothelial growth factor (VEGF), insulin-like growth factor
(IGF), connective
tissue growth factor (CTGF), activin, interleukin-1 (ILla, IL1f3), TNFa, GM-
CSF, or autologous
intraoperative biologics such as platelet-rich plasma (PRP) and bone marrow
(BM).
[0022] In other embodiments, the petrolatum-based compositions described
herein may
further comprise a dermatologically acceptable carrier. A "dermatologically-
acceptable carrier,"
as used herein, is a component or components suitable for use in contact with
human keratinous
tissue without undue toxicity, incompatibility, instability, allergic
response, and the like. Where
employed, the carrier is inert in the sense of not bringing about a
deactivation of the active
ingredients, and in the sense of not bringing about any adverse effect on the
skin areas to which
it is applied. Common dermatological additives are also envisioned for some
embodiments. In
certain embodiments, a dermatological additive is a whitening agent and/or
hemostatic agent.
[0023] Additionally, the presently-disclosed compositions may be incorporated
in
predetermined therapeutically effective amounts into disposables such as
wipes, gauze, patches,
wraps, bandages, adhesive strips, sponge, cotton swab, glove, sock, wrist
bands, fabric, fibers,
sutures, medication pad, underwear, tissue, pain-relief gel pack or bed liner
and the like. For
instance, the composition may be applied to the surface of, or impregnated
into disposables.
II. PROCESS FOR MAKING
[0024] The present disclosure also provides a method for making the
compositions
described in Section (I). The process comprises: (a) dissolving one or more
anti-fungal agents in
a solvent to give an anti-fungal agent solution; (b) heating the petrolatum to
a temperature
sufficient to give a melted petrolatum, and heating the anti-fungal agent
solution to a temperature
higher than the temperature of the petrolatum to give a heated anti-fungal
agent solution; (c)
mixing the melted petrolatum and the heated anti-fungal agent solution to give
a melted mixture;
and, (d) cooling the melted mixture to give the petrolatum-based composition.
As would be
appreciated by one of skill in the art, steps (a) ¨ (d) are conducted
sequentially.
[0025] The one or more anti-fungal agents as well the optional cationic
biocide,
selected from the group described in Section (I), is first dissolved in a
solvent to give a anti-
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fungal agent solution. Acceptable solvents for the anti-fungal agent solution
include water or
other solvents. Generally polar solvents are used. The anti-fungal agents and
optional cationic
biocides are typically dissolved in the solvent a concentration ranging from
about 0.05% to about
5%. Typically, the amount of solvent used is from about 1:10 to about 1:30 the
amount of
petrolatum and more preferably is about 1:20 to the amount of petrolatum by
volume. The
amount of one or more anti-fungal agents and optional cationic biocides can be
calculated by one
skilled in the art to provide the desired weight percentage for the final
composition.
[0026] Both the anti-fungal agent solution and the petrolatum are heated. The
heating
of these two ingredients can be conducted at the same time or sequentially so
long as the melted
petrolatum and the heated anti-fungal agent solution are at the appropriate
temperatures during
the mixing step. Petrolatum is a solid that melts at approximately 37 C. As
such, petrolatum
may be heated to any temperature at or above 37 C. For instance, the
petrolatum may be heated
to a temperature ranging from about 37 C to about 45 C, from about 40 C to
about 50 C, from
about 45 C to about 55 C, from about 50 C to about 60 C, from about 55 C to
about 65 C, from
about 60 C to about 70 C, from about 65 C to about 75 C, from about 70 C to
about 80 C, from
about 75 C to about 85 C, from about 80 C to about 90 C, from about 85 C to
about 95 C, or
from about 90 C to about 100 C or more. Higher temperatures may also be
envisioned.
Preferably, the petrolatum is heated to a temperature ranging from about 37 C
to about 55 C,
more preferably to a temperature ranging from about 40 C to about 50 C. Heat
may be provided
to the petrolatum by any method known in the art, but a water bath or low
temperature hot plate
are preferred.
[0027] The anti-fungal agent solution is heated to a temperature above the
temperature
of the melted petrolatum. Any temperature above the temperature of the melted
petrolatum may
be used in a method of the present disclosure, provided that the heat does not
cause excessive
degradation of an active ingredient such as the one or more anti-fungal
agents, or excessive
evaporation of the active ingredient or polar solvent. For instance, the anti-
fungal agent solution
may be heated to a temperature that is about 1 C to about 10 C, about 5 C to
about 15 C, about
C to about 20 C, about 15 C to about 25 C, about 20 C to about 30 C, about 25
C to about
35 C, about 30 C to about 40 C, about 35 C to about 45 C, about 40 C to about
50 C, about
45 C to about 55 C, about 50 C to about 60 C or about 65 C or about 75 C
higher than the
temperature of the melted petrolatum. Higher temperatures may also be
envisioned. Preferably,
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the anti-fungal agent solution is heated to a temperature that is about 1 C to
about 10 C higher
than the temperature of the melted petrolatum. In another embodiment, the anti-
fungal agent
solution is heated to a temperature that is about 1 C to about 5 C higher than
the melted
petrolatum. In still other embodiments, the anti-fungal agent solution is
heated to a temperature
that is about 1 C, 2 C, 3 C, 4 C, or 5 C above the temperature of the melted
petrolatum. Again,
the heating can be provided by any means known in the art but is preferably
provided by a water
bath or low temperature hot plate.
[0028] Once both the petrolatum and the anti-fungal agent solution are heated
as
described above, the melted petrolatum and the heated anti-fungal agent
solution are mixed to
give a melted mixture containing petrolatum and the heated anti-fungal agent
solution. The
mixing can be accomplished by a variety of methods including homogenization,
acoustic mixing,
and high RPM mixing. Depending on the batch size, the size of the mixer, and
the type of
mixing, the mixing may be conducted for several minutes or more. When mixed in
accordance
with the parameters disclosed above, the melted petrolatum and the heated anti-
fungal agent
solution fuse in the melted mixture.
[0029] After the melted petrolatum and the heated anti-fungal agent solution
have fused
they are allowed to cool and solidify into the composition described more
fully in Section (I)
("the final composition"). Cooling may be achieved by reducing the amount of
heat provided to
the melted mixture, or cooling may be achieved passively under conditions
where no heating is
added. In some embodiments, cooling is controlled so that the temperature of
the melting
mixture is gradually lowered to ambient temperatures. The product is
preferably packaged a few
degrees above its solidification point so that the packaging can be filled by
pouring the melted
mixture. The composition preferably solidifies to the final composition in the
package. The
package is sealed after this solidification.
[0030] The process may be conducted with one or more anti-fungal agents, and
optionally, one or more cationic biocides. The anti-fungal agents and
optionally the cationic
biocides may be dissolved in s solvent separately or may be dissolved in the
same solvent. The
addition of additional anti-fungal agents or optional cationic biocides does
not change the
process steps above.
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III. METHODS OF USE
[0031] In another aspect, the invention encompasses a method of preventing or
treating
onychomycosis in a subject using the compositions described herein.
[0032] The compositions may be applied topically to the nail of a subject in
need.
Subjects in need may be those having onychomycosis, including subjects having
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis. The onychomycosis may be caused by,
for
example, Trichophyton rubrum (T. rubrum) or Candida auris (C. auris),
including multi-drug
resistant C. auris. The subject is preferably human but the composition may
also be useful in
animals, particularly mammals, for example domestic animals, livestock, or
other types of
animals.
[0033] Typically, the composition is applied to the nail of the subject.
Application to
the nail includes application to a site having onychomycosis as well as to
sites that may be
susceptible to acquiring onychomycosis. Therefore, the presently disclosed
compositions may
be applied to skin or nails in order to prevent infection by the causative
agent responsible for
onychomycosis. The presently disclosed compositions may also be used as a
topical dressing to
a nail and/or skin of a subject in order to prevent or reduce the occurrence
of onychomycosis. As
used herein, the terms "applied to the nail" or "applying to the nail," in all
their forms, as used
throughout this disclosure in reference to applying the presently disclosed
compositions to the
nail of a subject, refers to all modes of administration of the compositions
to the nail and/or
nearby skin of a patient including topical administration of the compositions
directly to the nail
or surrounding skin of a subject or causing contact between the compositions
and the nail of a
subject through, for instance, a wrap, gauze, or bandage impregnated or
containing the presently
disclosed compositions.
[0034] The amount of composition applied in the methods described herein can
and
will vary depending on the condition being treated and the severity of that
condition. Generally,
the amount used is sufficient to cover the affected nail area with a thin
layer of the composition.
The composition is applied directly to the nail. In some embodiments, the
composition is spread
so that it forms a thin layer over the treatment area. In other embodiments,
the composition is
spread by a melting action that occurs as the warmth of the patient's nail and
surrounding skin
melts the petrolatum or pharmaceutically acceptable carrier. The composition
may be covered
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with a bandage after application. The compositions may also be impregnated
into a bandage or
other material that is applied to the treatment area.
[0035] The composition when applied to the nail and surrounding skin is non-
irritating
and non-cytotoxic. These properties allow the composition to be used on
sensitive treatment
areas. These characteristics also allow for use to treat or prevent
onychomycosis over a long
period, such as for example 2 weeks, 4 weeks, 6 weeks, 8 weeks, or longer
without irritation to
the treated area. It will be recognized however, that the compositions may be
used for shorter
periods of time if necessary.
[0036] The compositions are also capable of extended release of the one or
more anti-
fungal agents and optionally cationic biocides to the area of application.
"Extended release" as
used herein means that the compositions release anti-fungal agents and
optionally cationic
biocides to the application site over a period of time extending past twelve
hours. The time over
which the extended release is provided is variable depending on the amount of
the composition
that is applied, but in general, the release of anti-fungal agents and
optional cationic biocides is
extended beyond the initial application and anti-fungal agents and optional
cationic biocides has
been shown to be released for up to 1 week. This extended release allows the
composition to be
applied less frequently and improves patient compliance with the treatment.
[0037] The compositions of the present disclosure also offer kinetic release
when
applied to the skin or nails. Kinetic release means that the anti-fungal
agents and optional
cationic biocides are released to the treatment area more rapidly when the
treatment area is
hotter.
EXAMPLES
[0038] The following examples are included to demonstrate preferred
embodiments of
the disclosure. It should be appreciated by those of skill in the art that the
techniques disclosed in
the examples that follow represent techniques discovered by the inventors to
function well in the
practice of the disclosure, and thus can be considered to constitute preferred
modes for its
practice. However, those of skill in the art should, in light of the present
disclosure, appreciate
that many changes can be made in the specific embodiments which are disclosed
and still obtain
a like or similar result without departing from the spirit and scope of the
disclosure.
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Example 1. Exemplary Formulation Process: Petrolatum-Based Terbinafine HC1
Composition
[0039] Formulation 1 is prepared by adding 2540.3 pounds of white petrolatum
to a
tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Terbinafine HC1 and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Terbinafine HC1,
0.13% BZK,
and 4.67% water. The formulation is observed to be stable for at least 6
months. During the 6
month observation period, the anti-fungal solution remains substantially
suspended in the
petrolatum carrier thereby resulting in a composition suitable for therapeutic
use for the
treatment of onychomycosis by topical administration to the nail and
surrounding skin of a
subject in need thereof.
Example 2. Petrolatum-Based Compositions Comprising Terbinafine HC1
[0040]
Formulation 2 is prepared in accordance with the present disclosure by
mixing Terbinafine HC1 and water to form an anti-fungal agent solution. The
anti-fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Terbinafine HC1 composition is formed, which comprises from about 0.01% to
about 5% by
weight terbinafine HC1 and greater than 85% petrolatum. Optionally, one or
more cationic
biocides is added to the anti-fungal agent solution prior to mixing with the
melted petrolatum
such that the resultant stable petrolatum-based composition further includes
from about 0.001%
to about 0.15% cationic biocide.
Such cationic biocides may include, for example,
benzalkonium chloride, cetrimide, chlorhexidine, and any combination thereof.
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Example 3. Topical Administration of Petrolatum-Based Compositions Comprising
Terbinafine HCl Improves Clinical Outcomes in Subjects Having Onychomycosis
[0041] The effect of topical administration of Formulations 1 and 2
(petrolatum-
based compositions comprising Terbinafine HC1) in the treatment of human
subjects having
onychomycosis will be studied using a randomized, double-blind clinical study.
During the
clinical study, a group of human subjects will be topically administered the
compositions
corresponding to Formulations 1 and 2 of Examples 1 and 2. In particular, the
petrolatum-based
compositions comprising Terbinafine HC1 will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 4. Exemplary Formulation Process: Petrolatum-Based Ciclopirox
Composition
[0042] Formulation 3 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Ciclopirox and BZK to form an anti-fungal
agent solution.
The anti-fungal agent solution is heated to 122 F. With the melted petrolatum
at a temperature
from about 110 F to about 113 F and the anti-fungal agent solution at a
temperature of 122 F,
the anti-fungal agent solution is slowly added to the petrolatum while mixing.
After all of the
anti-fungal solution is added to the melted petrolatum at temperature, the
heat is decreased
slowly to from about 96 F to about 104 F. The resulting formulation contains
the following
ingredients by weight percent: 95% petrolatum, 0.2% Ciclopirox, 0.13% BZK, and
4.67% water.
The formulation is observed to be stable for at least 6 months. During the 6
month observation
period, the anti-fungal solution remains substantially suspended in the
petrolatum carrier thereby
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resulting in a composition suitable for therapeutic use for the treatment of
onychomycosis by
topical administration to the nail and surrounding skin of a subject in need
thereof.
Example 5. Petrolatum-Based Compositions Comprising Ciclopirox
[0043] Formulation 4 is prepared in accordance with the present
disclosure by
mixing Ciclopirox and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Ciclopirox composition is formed, which comprises from about 0.01% to about 5%
by weight
Ciclopirox and greater than 85% petrolatum. Optionally, one or more cationic
biocides is added
to the anti-fungal agent solution prior to mixing with the melted petrolatum
such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
Example 6. Topical Administration of Petrolatum-Based Compositions Comprising
Ciclopirox Improves Clinical Outcomes in Subjects Having Onychomycosis
[0044] The effect of topical administration of Formulations 3 and 4
(petrolatum-
based compositions comprising Ciclopirox) in the treatment of human subjects
having
onychomycosis will be studied using a randomized, double-blind clinical study.
During the
clinical study, a group of human subjects will be topically administered the
compositions
corresponding to Formulations 3 and 4 of Examples 4 and 5. In particular, the
petrolatum-based
compositions comprising Ciclopirox will be applied to the nail of a subject
having or otherwise
affected by onychomycosis. Subjects receiving such treatment will have
improved standard
clinical outcomes. In particular, subjects receiving treatment according to
the presently disclosed
methods and techniques are will exhibit a reduced rate of occurrence of
onychomycosis in the
nails or portions thereof receiving treatment as well as reduced clinical
signs of onychomycosis.
Similar improved standard clinical outcomes will be obtained for subjects
having onychomycosis
caused by T. rubrum, Candida, as well as for the distal subungual
onychomycosis, white
superficial onychomycosis (WSO), proximal subungual onychomycosis, and
Candidal
onychomycosis sub-types of onychomycosis.
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Example 7. Exemplary Formulation Process: Petrolatum-Based Ciclopirox Olamine
Composition
[0045] Formulation 5 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Ciclopirox Olamine and BZK to form an
anti-fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Ciclopirox
Olamine, 0.13%
BZK, and 4.67% water. The formulation is observed to be stable for at least 6
months. During
the 6 month observation period, the anti-fungal solution remains substantially
suspended in the
petrolatum carrier thereby resulting in a composition suitable for therapeutic
use for the
treatment of onychomycosis by topical administration to the nail and
surrounding skin of a
subject in need thereof.
Example 8. Petrolatum-Based Compositions Comprising Ciclopirox Olamine
[0046] Formulation 6 is prepared in accordance with the present
disclosure by
mixing Ciclopirox Olamine and water to form an anti-fungal agent solution. The
anti-fungal
agent solution is heated to a temperature from about 1 C to about 5 C higher
than the
temperature of the melted petrolatum and mixed. Upon allowing the mixture to
cool, a stable
petrolatum-based Ciclopirox Olamine composition is formed, which comprises
from about
0.01% to about 5% by weight Ciclopirox Olamine and greater than 85%
petrolatum. Optionally,
one or more cationic biocides is added to the anti-fungal agent solution prior
to mixing with the
melted petrolatum such that the resultant stable petrolatum-based composition
further includes
from about 0.001% to about 0.15% cationic biocide. Such cationic biocides may
include, for
example, benzalkonium chloride, cetrimide, chlorhexidine, and any combination
thereof.
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Example 9. Topical Administration of Petrolatum-Based Compositions Comprising
Ciclopirox Olamine Improves Clinical Outcomes in Subjects Having Onychomycosis
[0047] The effect of topical administration of Formulations 5 and 6
(petrolatum-
based compositions comprising Ciclopirox Olamine) in the treatment of human
subjects having
onychomycosis will be studied using a randomized, double-blind clinical study.
During the
clinical study, a group of human subjects will be topically administered the
compositions
corresponding to Formulations 5 and 6 of Examples 7 and 8. In particular, the
petrolatum-based
compositions comprising Ciclopirox Olamine will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 10. Exemplary Formulation Process: Petrolatum-Based Fluconazole
Composition
[0048] Formulation 7 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Fluconazole and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Fluconazole,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
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onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 11. Petrolatum-Based Compositions Comprising Fluconazole
[0049] Formulation 8 is prepared in accordance with the present
disclosure by
mixing Fluconazole and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Fluconazole composition is formed, which comprises from about 0.01% to about
5% by weight
Fluconazole and greater than 85% petrolatum. Optionally, one or more cationic
biocides is
added to the anti-fungal agent solution prior to mixing with the melted
petrolatum such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
Example 12. Topical Administration of Petrolatum-Based Compositions Comprising
Fluconazole Improves Clinical Outcomes in Subjects Having Onychomycosis
[0050] The effect of topical administration of Formulations 7 and 8
(petrolatum-
based compositions comprising Fluconazole) in the treatment of human subjects
having
onychomycosis will be studied using a randomized, double-blind clinical study.
During the
clinical study, a group of human subjects will be topically administered the
compositions
corresponding to Formulations 7 and 8 of Examples 10 and 11. In particular,
the petrolatum-
based compositions comprising Fluconazole will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
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Example 13. Exemplary Formulation Process: Petrolatum-Based Itraconazole
Composition
[0051] Formulation 9 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Itraconazole and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Itraconazole,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 14. Petrolatum-Based Compositions Comprising Itraconazole
[0052] Formulation 10 is prepared in accordance with the present
disclosure by
mixing Itraconazole and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Itraconazole composition is formed, which comprises from about 0.01% to about
5% by weight
Itraconazole and greater than 85% petrolatum. Optionally, one or more cationic
biocides is
added to the anti-fungal agent solution prior to mixing with the melted
petrolatum such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
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Example 15. Topical Administration of Petrolatum-Based Compositions Comprising
Itraconazole Improves Clinical Outcomes in Subjects Having Onychomycosis
[0053] The effect of topical administration of Formulations 9 and
10 (petrolatum-
based compositions comprising Itraconazole) in the treatment of human subjects
having
onychomycosis will be studied using a randomized, double-blind clinical study.
During the
clinical study, a group of human subjects will be topically administered the
compositions
corresponding to Formulations 9 and 10 of Examples 13 and 14. In particular,
the petrolatum-
based compositions comprising Itraconazole will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 16. Exemplary Formulation Process: Petrolatum-Based Ketoconazole
Composition
[0054] Formulation 11 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Ketoconazole and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Ketoconazole,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
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carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 17. Petrolatum-Based Compositions Comprising Ketoconazole
[0055] Formulation 12 is prepared in accordance with the present
disclosure by
mixing Ketoconazole and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Ketoconazole composition is formed, which comprises from about 0.01% to about
5% by weight
Ketoconazole and greater than 85% petrolatum. Optionally, one or more cationic
biocides is
added to the anti-fungal agent solution prior to mixing with the melted
petrolatum such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
Example 18. Topical Administration of Petrolatum-Based Compositions Comprising
Ketoconazole Improves Clinical Outcomes in Subjects Having Onychomycosis
[0056] The effect of topical administration of Formulations 11 and
12
(petrolatum-based compositions comprising Ketoconazole) in the treatment of
human subjects
having onychomycosis will be studied using a randomized, double-blind clinical
study. During
the clinical study, a group of human subjects will be topically administered
the compositions
corresponding to Formulations 11 and 12 of Examples 16 and 17. In particular,
the petrolatum-
based compositions comprising Ketoconazole will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
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subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 19. Exemplary Formulation Process: Petrolatum-Based Amorolfine
Composition
[0057] Formulation 13 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Amorolfine and BZK to form an anti-fungal
agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Amorolfine,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 20. Petrolatum-Based Compositions Comprising Amorolfine
[0058] Formulation 14 is prepared in accordance with the present
disclosure by
mixing Amorolfine and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Amorolfine composition is formed, which comprises from about 0.01% to about 5%
by weight
Amorolfine and greater than 85% petrolatum. Optionally, one or more cationic
biocides is added
to the anti-fungal agent solution prior to mixing with the melted petrolatum
such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
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Example 21. Topical Administration of Petrolatum-Based Compositions Comprising
Amorolfine Improves Clinical Outcomes in Subjects Having Onychomycosis
[0059] The effect of topical administration of Formulations 13 and
14
(petrolatum-based compositions comprising Amorolfine) in the treatment of
human subjects
having onychomycosis will be studied using a randomized, double-blind clinical
study. During
the clinical study, a group of human subjects will be topically administered
the compositions
corresponding to Formulations 13 and 14 of Examples 19 and 20. In particular,
the petrolatum-
based compositions comprising Amorolfine will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 22. Exemplary Formulation Process: Petrolatum-Based Efinaconazole
Composition
[0060] Formulation 15 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Efinaconazole and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Efinaconazole,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
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carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 23. Petrolatum-Based Compositions Comprising Efinaconazole
[0061]
Formulation 16 is prepared in accordance with the present disclosure by
mixing Efinaconazole and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Efinaconazole composition is formed, which comprises from about 0.01% to about
5% by
weight Efinaconazole and greater than 85% petrolatum. Optionally, one or more
cationic
biocides is added to the anti-fungal agent solution prior to mixing with the
melted petrolatum
such that the resultant stable petrolatum-based composition further includes
from about 0.001%
to about 0.15% cationic biocide.
Such cationic biocides may include, for example,
benzalkonium chloride, cetrimide, chlorhexidine, and any combination thereof.
Example 24. Topical Administration of Petrolatum-Based Compositions Comprising
Efinaconazole Improves Clinical Outcomes in Subjects Having Onychomycosis
[0062]
The effect of topical administration of Formulations 15 and 16
(petrolatum-based compositions comprising Efinaconazole) in the treatment of
human subjects
having onychomycosis will be studied using a randomized, double-blind clinical
study. During
the clinical study, a group of human subjects will be topically administered
the compositions
corresponding to Formulations 15 and 16 of Examples 22 and 23. In particular,
the petrolatum-
based compositions comprising Efinaconazole will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
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subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 25. Exemplary Formulation Process: Petrolatum-Based Clotrimazole
Composition
[0063] Formulation 17 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Clotrimazole and BZK to form an anti-
fungal agent
solution. The anti-fungal agent solution is heated to 122 F. With the melted
petrolatum at a
temperature from about 110 F to about 113 F and the anti-fungal agent solution
at a temperature
of 122 F, the anti-fungal agent solution is slowly added to the petrolatum
while mixing. After
all of the anti-fungal solution is added to the melted petrolatum at
temperature, the heat is
decreased slowly to from about 96 F to about 104 F. The resulting formulation
contains the
following ingredients by weight percent: 95% petrolatum, 0.2% Clotrimazole,
0.13% BZK, and
4.67% water. The formulation is observed to be stable for at least 6 months.
During the 6 month
observation period, the anti-fungal solution remains substantially suspended
in the petrolatum
carrier thereby resulting in a composition suitable for therapeutic use for
the treatment of
onychomycosis by topical administration to the nail and surrounding skin of a
subject in need
thereof.
Example 26. Petrolatum-Based Compositions Comprising Clotrimazole
[0064] Formulation 18 is prepared in accordance with the present
disclosure by
mixing Clotrimazole and water to form an anti-fungal agent solution. The anti-
fungal agent
solution is heated to a temperature from about 1 C to about 5 C higher than
the temperature of
the melted petrolatum and mixed. Upon allowing the mixture to cool, a stable
petrolatum-based
Clotrimazole composition is formed, which comprises from about 0.01% to about
5% by weight
Clotrimazole and greater than 85% petrolatum. Optionally, one or more cationic
biocides is
added to the anti-fungal agent solution prior to mixing with the melted
petrolatum such that the
resultant stable petrolatum-based composition further includes from about
0.001% to about
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0.15% cationic biocide. Such cationic biocides may include, for example,
benzalkonium
chloride, cetrimide, chlorhexidine, and any combination thereof.
Example 27. Topical Administration of Petrolatum-Based Compositions Comprising
Clotrimazole Improves Clinical Outcomes in Subjects Having Onychomycosis
[0065] The effect of topical administration of Formulations 17 and
18
(petrolatum-based compositions comprising Clotrimazole) in the treatment of
human subjects
having onychomycosis will be studied using a randomized, double-blind clinical
study. During
the clinical study, a group of human subjects will be topically administered
the compositions
corresponding to Formulations 17 and 18 of Examples 25 and 26. In particular,
the petrolatum-
based compositions comprising Clotrimazole will be applied to the nail of a
subject having or
otherwise affected by onychomycosis. Subjects receiving such treatment will
have improved
standard clinical outcomes. In particular, subjects receiving treatment
according to the presently
disclosed methods and techniques are will exhibit a reduced rate of occurrence
of
onychomycosis in the nails or portions thereof receiving treatment as well as
reduced clinical
signs of onychomycosis. Similar improved standard clinical outcomes will be
obtained for
subjects having onychomycosis caused by T. rubrum, Candida, as well as for the
distal
subungual onychomycosis, white superficial onychomycosis (WSO), proximal
subungual
onychomycosis, and Candidal onychomycosis sub-types of onychomycosis.
Example 28. Exemplary Formulation Process: Petrolatum-Based Miconazole
(Miconazole
Nitrate) Composition
[0066] Formulation 19 is prepared by adding 2540.3 pounds of white
petrolatum
to a tank that has been cleaned and sterilized. The petrolatum in the tanks is
heated to 110 C to
113 F in order to cause the petrolatum to melt. In a separate clean and
sanitized container
133.70 pounds of water is mixed with Miconazole (Miconazole Nitrate) and BZK
to form an
anti-fungal agent solution. The anti-fungal agent solution is heated to 122 F.
With the melted
petrolatum at a temperature from about 110 F to about 113 F and the anti-
fungal agent solution
at a temperature of 122 F, the anti-fungal agent solution is slowly added to
the petrolatum while
mixing. After all of the anti-fungal solution is added to the melted
petrolatum at temperature, the
heat is decreased slowly to from about 96 F to about 104 F. The resulting
formulation contains
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the following ingredients by weight percent: 95% petrolatum, 0.2% Miconazole
(Miconazole
Nitrate), 0.13% BZK, and 4.67% water. The formulation is observed to be stable
for at least 6
months. During the 6 month observation period, the anti-fungal solution
remains substantially
suspended in the petrolatum carrier thereby resulting in a composition
suitable for therapeutic
use for the treatment of onychomycosis by topical administration to the nail
and surrounding skin
of a subject in need thereof.
Example 29. Petrolatum-Based Compositions Comprising Miconazole (Miconazole
Nitrate)
[0067] Formulation 20 is prepared in accordance with the present
disclosure by
mixing Miconazole (Miconazole Nitrate) and water to form an anti-fungal agent
solution. The
anti-fungal agent solution is heated to a temperature from about 1 C to about
5 C higher than the
temperature of the melted petrolatum and mixed. Upon allowing the mixture to
cool, a stable
petrolatum-based Miconazole (Miconazole Nitrate) composition is formed, which
comprises
from about 0.01% to about 5% by weight Miconazole (Miconazole Nitrate) and
greater than 85%
petrolatum. Optionally, one or more cationic biocides is added to the anti-
fungal agent solution
prior to mixing with the melted petrolatum such that the resultant stable
petrolatum-based
composition further includes from about 0.001% to about 0.15% cationic
biocide. Such cationic
biocides may include, for example, benzalkonium chloride, cetrimide,
chlorhexidine, and any
combination thereof.
Example 30. Topical Administration of Petrolatum-Based Compositions Comprising
Miconazole (Miconazole Nitrate) Improves Clinical Outcomes in Subjects Having
Onychomycosis
[0068] The effect of topical administration of Formulations 19 and
20
(petrolatum-based compositions comprising Miconazole (Miconazole Nitrate)) in
the treatment
of human subjects having onychomycosis will be studied using a randomized,
double-blind
clinical study. During the clinical study, a group of human subjects will be
topically
administered the compositions corresponding to Formulations 19 and 20 of
Examples 28 and 29.
In particular, the petrolatum-based compositions comprising Miconazole
(Miconazole Nitrate)
will be applied to the nail of a subject having or otherwise affected by
onychomycosis. Subjects
receiving such treatment will have improved standard clinical outcomes. In
particular, subjects
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receiving treatment according to the presently disclosed methods and
techniques are will exhibit
a reduced rate of occurrence of onychomycosis in the nails or portions thereof
receiving
treatment as well as reduced clinical signs of onychomycosis. Similar improved
standard clinical
outcomes will be obtained for subjects having onychomycosis caused by T.
rubrum, Candida, as
well as for the distal subungual onychomycosis, white superficial
onychomycosis (WSO),
proximal subungual onychomycosis, and Candidal onychomycosis sub-types of
onychomycosis.
STATEMENTS OF THE DISCLOSURE:
[0069] Numerous examples are provided herein to enhance
understanding of the
present disclosure. A specific set of statements are provided as follows.
[0070] Statement 1: A method of treating onychomycosis in a
subject, the method
comprising applying a petrolatum-based composition to the nail of a subject in
need of treatment,
wherein the petrolatum-based composition comprises one or more anti-fungal
agents and a
petrolatum carrier.
[0071] Statement 2: The method according to Statement 2, wherein
the one or
more anti-fungal agents is dispersed in the petrolatum carrier to form a
stable petrolatum-based
suspension.
[0072] Statement 3: The method according to Statement 1 or
Statement 2,
wherein the one or more anti-fungal agents is dispersed in the petrolatum
carrier in the form of
nanodroplets.
[0073] Statement 4: The method according to any one of Statements 1-
3, wherein
the petrolatum-based composition comprises nanodroplets dispersed in the
petrolatum carrier,
wherein the nanodroplets comprises one or more fungal agents and a polar
solvent.
[0074] Statement 5: The method according to any one of Statements 1-
4, wherein
the one or more anti-fungal agents is dissolved in a polar solvent to form an
anti-fungal agent
solution, the anti-fungal agent solution dispersed in the petrolatum to form a
stable suspension.
[0075] Statement 6: The method according to Statement 5, wherein
the anti-
fungal agent solution is dispersed in the petrolatum in the form of
nanodroplets.
[0076] Statement 7: The method according to any one of Statements 1-
6, wherein
the one or more anti-fungal agents is selected from the group consisting of
terbinafine HC1,
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ciclopirox, ciclopirox olamine, fluconazole, itraconazole, ketoconazole,
amorolfine,
efinaconazole, clotrimazole, miconazole (miconazole nitrate), and any
combination thereof.
[0077] Statement 8: The method according to any one of Statements 1-
7, wherein
the onychomycosis is caused by Trichophyton rubrum (T. rubrum).
[0078] Statement 9: The method according to any one of Statements 1-
7, wherein
the onychomycosis is caused by Candida.
[0079] Statement 10: The method according to any one of Statements
1-7,
wherein the onychomycosis is distal subungual onychomycosis.
[0080] Statement 11: The method according to any one of Statements
1-7,
wherein the onychomycosis is white superficial onychomycosis (WSO).
[0081] Statement 12: The method according to any one of Statements
1-7,
wherein the onychomycosis is proximal subungual onychomycosis.
[0082] Statement 13: The method according to any one of Statements
1-7,
wherein the onychomycosis is Candidal onychomycosis.
[0083] Statement 14: The method according to Statement 13, wherein
the
Candidal onychomycosis is caused by Candida auris (C. auris).
[0084] Statement 15: The method according to Statement 14, wherein
the C. auris
is multi-drug resistant C. auris.
[0085] Statement 16: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
5% by weight
of the petrolatum-based composition.
[0086] Statement 17: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
3% by weight
of the petrolatum-based composition.
[0087] Statement 18: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.1% to about
1% by weight of
the petrolatum-based composition.
[0088] Statement 19: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.2% to about
0.6% by weight
of the petrolatum-based composition.
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[0089] Statement 20: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.3% to about
0.5% by weight
of the petrolatum-based composition.
[0090] Statement 21: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.1% to about
3.5% by weight
of the petrolatum-based composition.
[0091] Statement 22: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
2.5% by
weight of the petrolatum-based composition.
[0092] Statement 23: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.5% to about
3% by weight of
the petrolatum-based composition.
[0093] Statement 24: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 0.5% to about
2.5% by weight
of the petrolatum-based composition.
[0094] Statement 25: The method according to any one of Statements
1-15,
wherein the one or more anti-fungal agents comprises from about 1.5% to about
2.5% by weight
of the petrolatum-based composition.
[0095] Statement 26: The method according to any one of Statements
1-25,
wherein the petrolatum-based composition comprises greater than about 80% by
weight
petrolatum.
[0096] Statement 27: The method according to any one of Statements
1-25,
wherein the petrolatum-based composition comprises greater than about 90% by
weight
petrolatum.
[0097] Statement 28: The method according to any one of Statements
1-25,
wherein the petrolatum-based composition comprises greater than about 95% by
weight
petrolatum.
[0098] Statement 29: The method according to any one of Statements
1-28,
wherein the petrolatum-based composition contains no emulsifier.
[0099] Statement 30: The method according to any one of Statements
1-28,
wherein the petrolatum-based composition excludes an added emulsifier.
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[00100] Statement 31: The method according to any one of Statements
1-30,
wherein the petrolatum-based composition further includes a cationic biocide
selected from the
group consisting of benzalkonium chloride, cetrimide, chlorhexidine, and any
combination
thereof.
[00101] Statement 32: The method according to Statement 31, wherein
the
petrolatum-based composition comprises from about 0.001% to about 0.15% by
weight
benzalkonium chloride (BZK).
[00102] Statement 33: The method according to Statement 31, wherein
the
petrolatum-based composition comprises from about 0.001% to about 0.01% or
from about
0.005% to about 0.007% by weight benzalkonium chloride (BZK).
[00103] Statement 34: The method according to any one of Statements
1-33,
wherein the petrolatum-based composition is prepared by a process comprising:
a) dissolving the
one or more anti-fungal agents in a polar solvent to give an anti-fungal agent
solution; b) heating
the petrolatum to a temperature sufficient to cause the petrolatum to melt to
give a melted
petrolatum and heating the anti-fungal agent solution to a temperature higher
than the
temperature of the melted petrolatum to give a heated anti-fungal agent
solution; c) mixing the
melted petrolatum and the heated anti-fungal agent solution to give a melted
mixture; and d)
cooling the melted mixture to give the petrolatum-based composition.
[00104] Statement 35: The method according to Statement 34, wherein
the heated
anti-fungal agent solution has a temperature that is about 1 C to about 5 C
higher than the
temperature of the melted petrolatum.
[00105] Statement 36: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
terbinafine HC1.
[00106] Statement 37: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ciclopirox.
[00107] Statement 38: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ciclopirox olamine.
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[00108] Statement 39: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
fluconazole.
[00109] Statement 40: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
itraconazole.
[00110] Statement 41: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ketoconazole.
[00111] Statement 42: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
amorolfine.
[00112] Statement 43: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
efinaconazole.
[00113] Statement 44: A petrolatum-based composition for the
treatment of
onychomycosis, the composition comprising a pharmaceutically effective amount
of one or more
anti-fungal agents in a petrolatum carrier.
[00114] Statement 45: The composition according to Statement 44,
wherein the
one or more anti-fungal agents is dispersed in the petrolatum carrier to form
a stable petrolatum-
based suspension.
[00115] Statement 46: The composition according to Statement 44 or
Statement
45, wherein the one or more anti-fungal agents is dispersed in the petrolatum
carrier in the form
of nanodroplets.
[00116] Statement 47: The composition according to any one of
Statements 44-46,
wherein the petrolatum-based composition comprises nanodroplets dispersed in
the petrolatum
carrier, wherein the nanodroplets comprises one or more fungal agents and a
polar solvent.
[00117] Statement 48: The composition according to any one of
Statements 44-47,
wherein the one or more anti-fungal agents is dissolved in a polar solvent to
form an anti-fungal
agent solution, the anti-fungal agent solution dispersed in the petrolatum to
form a stable
suspension.
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[00118] Statement 49: The composition according to Statement 48,
wherein the
anti-fungal agent solution is dispersed in the petrolatum in the form of
nanodroplets.
[00119] Statement 50: The composition according to any one of
Statements 44-49,
wherein the one or more anti-fungal agents is selected from the group
consisting of terbinafine
HC1, ciclopirox, ciclopirox olamine, fluconazole, itraconazole, ketoconazole,
amorolfine,
efinaconazole, clotrimazole, miconazole (miconazole nitrate), and any
combination thereof.
[00120] Statement 51: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is caused by Trichophyton rubrum (T. rubrum).
[00121] Statement 52: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is caused by Candida.
[00122] Statement 53: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is distal subungual onychomycosis.
[00123] Statement 54: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is white superficial onychomycosis (WSO).
[00124] Statement 55: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is proximal subungual onychomycosis.
[00125] Statement 56: The composition according to any one of
Statements 44-50,
wherein the onychomycosis is Candidal onychomycosis.
[00126] Statement 57: The composition according to Statement 56,
wherein the
Candidal onychomycosis is caused by Candida auris (C. auris).
[00127] Statement 58: The composition according to Statement 57,
wherein the C.
auris is multi-drug resistant C. auris.
[00128] Statement 59: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
5% by weight
of the petrolatum-based composition.
[00129] Statement 60: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
3% by weight
of the petrolatum-based composition.
[00130] Statement 61: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.1% to about
1% by weight of
the petrolatum-based composition.
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[00131] Statement 62: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.2% to about
0.6% by weight
of the petrolatum-based composition.
[00132] Statement 63: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.3% to about
0.5% by weight
of the petrolatum-based composition.
[00133] Statement 64: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.1% to about
3.5% by weight
of the petrolatum-based composition.
[00134] Statement 65: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.05% to about
2.5% by
weight of the petrolatum-based composition.
[00135] Statement 66: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.5% to about
3% by weight of
the petrolatum-based composition.
[00136] Statement 67: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 0.5% to about
2.5% by weight
of the petrolatum-based composition.
[00137] Statement 68: The composition according to any one of
Statements 44-58,
wherein the one or more anti-fungal agents comprises from about 1.5% to about
2.5% by weight
of the petrolatum-based composition.
[00138] Statement 69: The composition according to any one of
Statements 44-68,
wherein the petrolatum-based composition comprises greater than about 80% by
weight
petrolatum.
[00139] Statement 70: The composition according to any one of
Statements 44-68,
wherein the petrolatum-based composition comprises greater than about 90% by
weight
petrolatum.
[00140] Statement 71: The composition according to any one of
Statements 44-68,
wherein the petrolatum-based composition comprises greater than about 95% by
weight
petrolatum.
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[00141] Statement 72: The composition according to any one of
Statements 44-71,
wherein the petrolatum-based composition contains no emulsifier.
[00142] Statement 73: The composition according to any one of
Statements 44-71,
wherein the petrolatum-based composition excludes an added emulsifier.
[00143] Statement 74: The composition according to any one of
Statements 44-73,
wherein the petrolatum-based composition further includes a cationic biocide
selected from the
group consisting of benzalkonium chloride, cetrimide, chlorhexidine, and any
combination
thereof.
[00144] Statement 75: The composition according to Statement 74,
wherein the
petrolatum-based composition comprises from about 0.001% to about 0.15% by
weight
benzalkonium chloride (BZK).
[00145] Statement 76: The composition according to Statement 74,
wherein the
petrolatum-based composition comprises from about 0.001% to about 0.01% or
from about
0.005% to about 0.007% by weight benzalkonium chloride (BZK).
[00146] Statement 77: The composition according to any one of
Statements 44-76,
wherein the petrolatum-based composition is prepared by a process comprising:
a) dissolving the
one or more anti-fungal agents in a polar solvent to give an anti-fungal agent
solution; b) heating
the petrolatum to a temperature sufficient to cause the petrolatum to melt to
give a melted
petrolatum and heating the anti-fungal agent solution to a temperature higher
than the
temperature of the melted petrolatum to give a heated anti-fungal agent
solution; c) mixing the
melted petrolatum and the heated anti-fungal agent solution to give a melted
mixture; and d)
cooling the melted mixture to give the petrolatum-based composition.
[00147] Statement 78: The composition according to Statement 77,
wherein the
heated anti-fungal agent solution has a temperature that is about 1 C to about
5 C higher than the
temperature of the melted petrolatum.
[00148] Statement 79: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
terbinafine HC1.
[00149] Statement 80: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ciclopirox.
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[00150] Statement 81: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ciclopirox olamine.
[00151] Statement 82: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
fluconazole.
[00152] Statement 83: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
itraconazole.
[00153] Statement 84: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
ketoconazole.
[00154] Statement 85: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
amorolfine.
[00155] Statement 86: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
efinaconazole.
[00156] Statement 87: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
clotrimazole.
[00157] Statement 88: The composition according to any one of
Statements 44-78,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
miconazole (miconazole nitrate).
[00158] Statement 89: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
clotrimazole.
[00159] Statement 90: The method according to any one of Statements
1-35,
wherein the petrolatum-based composition comprises from about 0.01% to about
5% by weight
miconazole (miconazole nitrate).
36
